Novel anhydrolide derivatives having antibacterial activity

ABSTRACT

Novel 11-12 substituted lactone anhydrolide derivatives and pharmaceutically-acceptable compositions comprising a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically-acceptable carrier are described. Also described are a method for treating bacterial infections by administering to an animal a pharmaceutical composition containing a therapeutically effective amount of a compound of the invention and processes for the preparation of such compounds.

REFERENCE TO RELATED APPLICATION

[0001] This application is a continuation of application Ser. No.10/289,820 (filed Nov. 7, 2002), which is incorporated herein byreference in its entirety.

TECHNICAL FIELD

[0002] The present invention relates to novel macrolides havingantibacterial activity and useful in the treatment and prevention ofbacterial infections. More particularly, the invention relates to novel11,12-lactone anhydrolides, a 14-membered macrolides, compositionscontaining such compounds and methods for using the same, as well asprocesses for making such compounds.

BACKGROUND OF THE INVENTION

[0003] Macrolide antibiotics play a therapeutically important role,particularly with the emergence of new pathogens. Structural differencesare related to the size of the lactone ring and to the number and nature(neutral or basic) of the sugars. Macrolides are classified according tothe size of the lactone ring (12, 14, 15 or 16 atoms). The macrolideantibiotic families (14-, 15- and 16-membered ring derivatives) exhibita wide range of characteristics (antibacterial spectrum, side-effectsand bioavailability). Among the commonly used macrolides areerythromycin, clarithromycin and azithromycin.

[0004] Erythromycins A through D, represented by formula (E) asillustrated below, (E)

Erythromycin R^(a) R^(b) A —OH —CH3 B —H —CH3 C —OH —H D —H —H

[0005] are well-known and potent antibacterial agents and are usedwidely to treat and prevent bacterial infection. As with otherantibacterials, however, bacterial strains having resistance orinsufficient susceptibility to erythromycin have been identified. Also,erythromycin A has only weak activity against Gram-negative bacteria.Therefore, there is a continuing need to identify new erythromycinderivative compounds which possess improved antibacterial activity,which have less potential for developing resistance, which possess thedesired Gram-negative activity, or which possess unexpected selectivityagainst target microorganisms. Consequently, numerous investigators haveprepared chemical derivatives of erythromycin in an attempt to obtainanalogs having modified or improved profiles of antibiotic activity.

[0006] International Application WO 97/42205 of Elliott et al, publishedNov. 13, 1997, discloses 3-descladinose-2,3-anhydroerythromycinderivatives having a cyclic carbamate and cyclic carbazate basic nuclearstructure. Further details were also disclosed in J. Med Chem., 41, pp1651-1659 (1998) and J. Med Chem., 41, pp 1660-1670 (1998) by Elliott etal, and by Griesgraber et al, respectively.

[0007] Erythromycin derivatives containing an 11,12-γ-lactone moiety aredisclosed in International Applications WO 02/16380, WO 02/50091, and WO02/50092.

SUMMARY OF THE INVENTION

[0008] The present invention provides a novel class of 14-memberedmacrolide compounds possessing antibacterial activity toward Grampositive and Gram negative bacteria as well as macrolide resistant Grampositives. The compounds of the present invention are represented by thegeneral formula (I) as illustrated below

[0009] as well as the pharmaceutically acceptable salts, esters orprodrugs thereof.

[0010] In formula (I) above:

[0011] L is selected from the group consisting of:

[0012] (1) —CH(OH)CH₃;

[0013] (2) C₁-C₆ alkyl, optionally substituted with one or moresubstituents selected from the group consisting of aryl, substitutedaryl, heteroaryl and substituted heteroaryl;

[0014] (3) C₂-C₆ alkenyl, optionally substituted with one or moresubstituents selected from the group consisting of aryl, substitutedaryl, heteroaryl and substituted heteroaryl; and

[0015] (4) C₂-C₆ alkynyl, optionally substituted with one or moresubstituents selected from the group consisting of aryl, substitutedaryl, heteroaryl and substituted heteroaryl;

[0016] R₁ is selected from the group consisting of C₁-C₆-alkyl,C₂-C₆-alkenyl and C₂-C₆-alkynyl, each optionally substituted with one ormore substituents selected from the group consisting of:

[0017] (1) halogen;

[0018] (2) aryl;

[0019] (3) substituted aryl;

[0020] (4) heteroaryl;

[0021] (5) substituted heteroaryl;

[0022] (6) —O—R₅, where R₅ is selected from the group consisting of:

[0023] a. hydrogen;

[0024] b. aryl;

[0025] c. substituted aryl;

[0026] d. heteroaryl; and

[0027] e. substituted heteroaryl;

[0028] (7) —O—C₁-C₆-alkyl-R₅, where R₅ is as previously defined;

[0029] (8) —O—C₂-C₆-alkenyl-R₅, where R₅ is as previously defined;

[0030] (9) —O—C₂-C₆-alkynyl-R₅, where R₅ is as previously defined; and

[0031] (10) —NR₆R₇, where R₆ and R₇ are each independently selected fromthe group consisting of: hydrogen; C₁-C₆-alkyl, optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, aryl, substituted aryl, heterocyclic and substitutedheterocyclic; C₂-C₆-alkenyl, optionally substituted with one or moresubstituents selected from the group consisting of halogen, aryl,substituted aryl, heterocyclic and substituted heterocyclic; andC₂-C₆-alkynyl, optionally substituted with one or more substituentsselected from the group consisting of halogen, aryl, substituted aryl,heterocyclic and substituted heterocyclic; or R₆R₇ taken together withthe nitrogen atom to which they are attached form a 3- to 7-memberedring which may optionally contain one or more hetero functions selectedfrom the group consisting of —O—, —NH—, —N(C₁-C₆-alkyl)-, —N(aryl)-,—N(heteroaryl)-, —S—, —S(O)— and —S(O)₂—;

[0032] R₂ is selected from the group consisting of:

[0033] (1) hydrogen;

[0034] (2) C₁-C₆-alkyl, optionally substituted with one or moresubstituents selected from the group consisting of:

[0035] a. halogen;

[0036] b. aryl;

[0037] c. substituted aryl;

[0038] d. heterocyclic;

[0039] e. substituted heterocyclic;

[0040] f. —O—R₃, where R₃ is selected from the group consisting of:

[0041] i. hydrogen;

[0042] ii. aryl;

[0043] iii. substituted aryl;

[0044] iv. heteroaryl; and

[0045] v. substituted heteroaryl;

[0046] g. —O—C₁-C₆-alkyl-R₃, where R₃ is as previously defined;

[0047] h. —O—C₂-C₆-alkenyl-R₃, where R₃ is as previously defined;

[0048] i. —O—C₂-C₆-alkynyl-R₃, where R₃ is as previously defined; and

[0049] j. —NR₆R₇, where R₆ and R₇ are as previously defined;

[0050] (3) C₂-C₆-alkenyl, optionally substituted with one or moresubstituents selected from the group consisting of:

[0051] a. halogen;

[0052] b. aryl;

[0053] c. substituted aryl;

[0054] d. heterocyclic;

[0055] e. substituted heterocyclic;

[0056] f. —O—R₃, where R₃ is as previously defined;

[0057] g. —O—C₁-C₆-alkyl-R₃, where R₃ is as previously defined;

[0058] h. —O—C₂-C₆-alkenyl-R₃, where R₃ is as previously defined;

[0059] i. —O—C₂-C₆-alkynyl-R₃, where R₃ is as previously defined; and

[0060] j. —NR₆R₇, where R₆ and R₇ are as previously defined; and

[0061] (4) C₂-C₆-alkynyl, optionally substituted with one or moresubstituents selected from the group consisting of:

[0062] a halogen;

[0063] b. aryl;

[0064] c. substituted aryl;

[0065] d. heterocyclic;

[0066] e. substituted heterocyclic;

[0067] f. —O—R₃, where R₃ is as previously defined;

[0068] g. —O—C₁-C₆-alkyl-R₃, where R₃ is as previously defined;

[0069] h. —O—C₂-C₆-alkenyl-R₃, where R₃ is as previously defined;

[0070] i. —O—C₂-C₆-alkynyl-R₃, where R₃ is as previously defined; and

[0071] j. —NR₆R₇, where R₆ and R₇ are as previously defined;

[0072] X is selected from the group consisting of:

[0073] (a) S(O)_(n), where n is 0, 1, or 2;

[0074] (b) O; and

[0075] (c) NR₅, where R₅ is as previously defined;

[0076]  and

[0077] Rp is hydrogen or a hydroxy protecting group.

[0078] In another aspect of the present invention there are disclosedpharmaceutical compositions comprising a therapeutically effectiveamount of a compound of the invention in combination with apharmaceutically acceptable carrier and treatment of bacterialinfections with such compositions. Suitable carriers and methods offormulation are also disclosed. The compounds and compositions of thepresent invention have antibacterial activity.

[0079] In a further aspect of the present invention there are providedprocesses for the preparation of bicyclic macrolide derivatives offormula (I) wherein L, X, R₁, R₂ and Rp are as previously described.

DETAILED DESCRIPTION OF THE INVENTION

[0080] A first embodiment of the present invention includes compoundsrepresented by formula (I), as illustrated above, as well as thepharmaceutically acceptable salts, esters and prodrugs thereof.

[0081] A preferred group of compounds of the present invention are thoserepresented by formula (I) wherein L is ethyl, X is sulfur, R₁ ismethyl, and where R₂ and Rp are as previously defined.

[0082] Representative compounds of the invention are those selected fromthe group consisting of:

[0083] Compound of formula (I): L=CH₂CH₃, X=S, R₁=CH₃,R₂=2-[6-(dimethylamino-methyleneamino)purin-9-yl]-ethyl and Rp=H;

[0084] Compound of formula (1): L=CH₂CH₃, X=S, R₁=CH₃,R₂=2-(6-amino-purin-yl)-ethyl and Rp=H;

[0085] Compound of formula (1): L=CH₂CH₃, X=S, R₁=CH₃,R₂=3-(3-pyridinyl)-1H-pyrazole-ethyl and Rp=H;

[0086] Compound of formula (I): L=CH₂CH₃, X=S, R₁=CH₃,R₂=[3-(3-pyridinyl)-1H-1,2,4 triazole-1-yl]-ethyl and Rp=H;

[0087] Compound of formula (1): L=CH₂CH₃, X=S, R₁=CH₃,R₂==[4(3-pyridinyl)-1H-imidazole]-1-ethyl and Rp=H; and

[0088] Compound of formula (1): L=CH₂CH₃, X=0, R₁=CH₃, R₂=CH₂CH₂-phenyland Rp=H.

[0089] Definitions

[0090] The terms “C₁-C₃ alkyl,” “C₁-C₆ alkyl” or “C₁-C₁₂ alkyl,” as usedherein, refer to saturated, straight- or branched-chain hydrocarbonradicals containing between one and three, one and six, or one andtwelve carbon atoms, respectively. Examples of C₁-C₃ alkyl radicalsinclude methyl, ethyl, propyl and isopropyl radicals; examples of C₁-C₆alkyl radicals include, but are not limited to, methyl, ethyl, propyl,isopropyl, n-butyl, tert-butyl, neopentyl and n-hexyl radicals; andexamples of C₁-C₁₂ alkyl radicals include, but are not limited to,methyl, ethyl, n-propyl, isopropyl, n-hexyl, n-octyl, n-decyl andn-dodecyl radicals.

[0091] The terms “C₂-C₆ alkenyl” or “C₂-C₁₂ alkenyl,” as used herein,denote a monovalent group derived from a hydrocarbon moiety containingfrom two to six or two to twelve carbon atoms having at least onecarbon-carbon double bond by the removal of a single hydrogen atom.Alkenyl groups include, but are not limited to, ethenyl, propenyl,isobutenyl, 1,3-hexadienyl, n-hexenyl, 3-pentenyl,1-methyl-2-buten-1-yl, and the like.

[0092] The terms “C₂-C₆ alkynyl” or “C₂-C₁₂ alkynyl,” as used herein,denote a monovalent group derived from a hydrocarbon moiety containingfrom two to six or two to twelve carbon atoms having at least onecarbon-carbon triple bond by the removal of two hydrogen atoms.Representative alkynyl groups include, but are not limited to, ethynyl,1-propynyl, 1-butynyl, isopentynyl, 1,3-hexadiynyl, n-hexynyl,3-pentynyl, 1-hexen-3-ynyl and the like.

[0093] The terms “halo” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine and iodine.

[0094] The term “haloalkyl” denotes an alkyl group, as defined above,having one, two or three halogen atoms attached thereto and isexemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl,and the like.

[0095] The term “aryl,” as used herein, refers to a mono-, bicyclic ortricyclic carbocyclic ring system having one, two or three aromaticrings including, but not limited to, phenyl, naphthyl, anthryl, azulyl,tetrahydronaphthyl, indanyl, indenyl and the like.

[0096] The term “substituted aryl,” as used herein, refers to an arylgroup, as defined herein, substituted by independent replacement of oneor more of the hydrogen atoms thereon with substituents independentlyselected from substituents such as, but not limited to, alkyl,haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino,acylamino, hydroxy, cyano, halo, mercapto, nitro, carboxaldehyde,carboxyl, alkoxycarbonyl, carboxamide, aryl, substituted aryl,heteroaryl, substituted heteroaryl, benzyl, benzyloxy, aryloxy,heteroaryloxy, C₁-C₆-alkoxy, methoxymethoxy, methoxyethoxy, amino,benzylamino, arylamino, heteroarylamino, C₁-C₃-alkylamino, thio,aryl-thio, heteroarylthio, benzyl-thio, C₁-C₆-alkyl-thio, ormethylthiomethyl. Representative substituents include, but are notlimited to, F, Cl, Br, I, OH, NO₂, CN, C(O)—C₁-C₆-alkyl, C(O)-aryl,C(O)-heteroaryl, CO₂-alkyl, CO₂-aryl, CO₂-heteroaryl, CONH₂,CONH—C₁-C₆-alkyl, CONH-aryl, CONH-heteroaryl, OC(O)—C₁-C₆-alkyl,OC(O)-aryl, OC(O)-heteroaryl, OCO2-alkyl, OCO2-aryl, OCO2-heteroaryl,OCONH₂, OCONH—C₁-C₆-alkyl, OCONH-aryl, OCONH-heteroaryl,NHC(O)—C₁-C₆-alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHCO₂-alkyl,NHCO₂-aryl, NHCO₂-heteroaryl, NHCONH₂, NHCONH—C₁-C₆-alkyl, NHCONH-aryl,NHCONH-heteroaryl, SO₂—C₁-C₆-alkyl, SO₂-aryl, SO₂-heteroaryl, SO₂NH₂,SO₂NH—C₁-C₆-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, C₁-C₆-alkyl,C₃-C₆-cycloalkyl, CF₃, CH₂CF₃, CH₂Cl₂, CH₂OH, CH₂CH₂OH, CH₂NH₂,CH₂SO₂CH₃, tetrafluorophenyl and pentafluorophenyl.

[0097] The term “heteroaryl,” as used herein, refers to a cyclicaromatic radical having from five to ten ring atoms of which one ringatom is selected from S, O and N; zero, one or two ring atoms areadditional heteroatoms independently selected from S, O and N; and theremaining ring atoms are carbon, the radical being joined to the rest ofthe molecule via any of the ring atoms, such as, for example, pyridinyl,pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl,oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl,quinolinyl, isoquinolinyl, and the like.

[0098] The term “substituted heteroaryl,” as used herein, refers to aheteroaryl group as defined herein, substituted by independentreplacement of one, or more of the hydrogen atoms thereon withsubstituents independently selected from substituents such as, but notlimited to, alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino,dialkylamino, acylamino, hydroxy, cyano, halo, mercapto, nitro,carboxaldehyde, carboxyl, alkoxycarbonyl, carboxamide, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, benzyl, benzyloxy, aryloxy,heteroaryloxy, C₁-C₆-alkoxy, methoxymethoxy, methoxyethoxy, amino,benzylamino, arylamino, heteroarylamino, C₁-C₃-alkylamino, thio,aryl-thio, heteroarylthio, benzyl-thio, C₁-C₆-alkyl-thio, ormethylthiomethyl. Representative substituents include, but are notlimited to, F, Cl, Br, I, OH, NO₂, CN, C(O)—C₁-C₆-alkyl, C(O)-aryl,C(O)-heteroaryl, CO₂-alkyl, CO₂-aryl, CO₂-heteroaryl, CONH₂,CONH—C₁-C₆-alkyl, CONH-aryl, CONH-heteroaryl, OC(O)—C₁-C₆-alkyl,OC(O)-aryl, OC(O)-heteroaryl, OCO₂-alkyl, OCO₂-aryl, OCO₂-heteroaryl,OCONH₂, OCONH—C₁-C₆-alkyl, OCONH-aryl, OCONH-heteroaryl,NHC(O)—C₁-C₆-alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHCO₂-alkyl,NHCO₂-aryl, NHCO₂-heteroaryl, NHCONH₂, NHCONH—C₁-C₆-alkyl, NHCONH-aryl,NHCONH-heteroaryl, SO₂—C₁-C₆-alkyl, SO₂-aryl, SO₂-heteroaryl, SO₂NH₂,SO₂NH—C₁-C₆-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, C₁-C₆-alkyl,C₃-C₆-cycloalkyl, CF₃, CH₂CF₃, CH₂Cl₂, CH₂OH, CH₂CH₂OH, CH₂NH₂,CH₂SO₂CH₃, tetrafluorophenyl and pentafluorophenyl.

[0099] The term “C₃-C₁₂-cycloalkyl”, as used herein, denotes amonovalent group derived from a monocyclic or bicyclic saturatedcarbocyclic ring compound having from 3 to 12 carbon atoms by theremoval of a single hydrogen atom. Examples include, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1]heptyl,and bicyclo [2.2.2] octyl.

[0100] The term “substituted C₃-C₁₂-Cycloalkyl”, as used herein, refersto a C₃-C₁₂-cycloalkyl group, as defined herein, substituted byindependent replacement of one or more of the hydrogen atoms thereinwith substituents independently selected from substituents such as, butnot limited to, alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino,dialkylamino, acylamino, hydroxy, cyano, halo, mercapto, nitro,carboxaldehyde, carboxyl, alkoxycarbonyl, carboxamide, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, benzyl, benzyloxy, aryloxy,heteroaryloxy, C₁-C₆-alkoxy, methoxymethoxy, methoxyethoxy, amino,benzylamino, arylamino, heteroarylamino, C₁-C₃-alkylamino, thio,aryl-thio, heteroarylthio, benzyl-thio, C₁-C₆-alkyl-thio, ormethylthiomethyl. Representative substituents include, but are notlimited to, F, Cl, Br, L OH, NO₂, CN, C(O)—C₁-C₆-alkyl, C(O)-aryl,C(O)-heteroaryl, CO₂-alkyl, CO₂-aryl, CO₂-heteroaryl, CONH₂,CONH—C₁-C₆-alkyl, CONH-aryl, CONH-heteroaryl, OC(O)—C₁-C₆-alkyl,OC(O)-aryl, OC(O)-heteroaryl, OCO₂-alkyl, OCO₂-aryl, OCO₂-heteroaryl,OCONH₂, OCONH—C₁-C₆-alkyl, OCONH-aryl, OCONH-heteroaryl,NHC(O)—C₁-C₆-alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHCO₂-alkyl,NHCO₂-aryl, NHCO₂-heteroaryl, NHCONH₂, NHCONH—C₁-C₆-alkyl, NHCONH-aryl,NHCONH-heteroaryl, SO₂—C₁-C₆-alkyl, SO₂-aryl, SO₂-heteroaryl, SO₂NH₂,SO₂NH—C₁-C₆-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, C₁-C₆-alkyl,C₃-C₆-Cycloalkyl, CF₃, CH₂CF₃, CH₂Cl₂, CH₂OH, CH₂CH₂OH, CH₂NH₂,CH₂SO₂CH₃, tetrafluorophenyl and pentafluorophenyl.

[0101] The term “C₁-C₃-alkyl-C₃-C₅-cycloalkyl”, as used herein, refersto a C₃-C₅ cycloalkyl radical, as defined herein, attached to aC₁-C₃-alkyl radical by replacement of a hydrogen atom on the latter.

[0102] The term “heterocycloalkyl,” as used herein, refers to anon-aromatic 3-, 4-, 5-, 6- or 7-membered ring or a bi- or tri-cyclicgroup comprising fused six-membered rings having between one and threeheteroatoms independently selected from oxygen, sulfur and nitrogen,wherein (i) each 5-membered ring has 0 to 1 double bonds and each6-membered ring has 0 to 2 double bonds, (ii) the nitrogen and sulfurheteroatoms may optionally be oxidized, (iii) the nitrogen heteroatommay optionally be quaternized, and (iv) any of the above heterocyclicrings may be fused to a benzene ring. Representative heterocyclesinclude, but are not limited to, pyrrolidinyl, pyrazolinyl,pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl,oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, and tetrahydrofuryl.

[0103] The term “substituted heterocycloalkyl”, as used herein, refersto a cycloalkyl group, as gefined herein, substituted by independentreplacement of one or more of the hydrogen atoms therein withsubstituents independently selected from substituents such as, but notlimited to, alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino,dialkylamino, acylamino, hydroxy, cyano, halo, mercapto, nitro,carboxaldehyde, carboxyl, alkoxycarbonyl, carboxamide, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, benzyl, benzyloxy, aryloxy,heteroaryloxy, C₁-C₆-alkoxy, methoxymethoxy, methoxyethoxy, amino,benzylamino, arylamino, heteroarylamino, C₁-C₃-alkylamino, thio,aryl-thio, heteroarylthio, benzyl-thio, C₁-C₆-alkyl-thio, ormethylthiomethyl. Representative substituents include, but are notlimited to, F, Cl, Br, I, OH, NO₂, CN, C(O)—C₁-C₆-alkyl, C(O)-aryl,C(O)-heteroaryl, CO₂-alkyl, CO₂-aryl, CO₂-heteroaryl, CONH₂,CONH—C₁-C₆-alkyl, CONH-aryl, CONH-heteroaryl, OC(O)—C₁-C₆-alkyl,OC(O)-aryl, OC(O)-heteroaryl, OCO₂-alkyl, OCO₂-aryl, OCO₂-heteroaryl,OCONH₂, OCONH—C₁-C₆-alkyl, OCONH-aryl, OCONH-heteroaryl,NHC(O)—C₁-C₆-alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHCO₂-alkyl,NHCO₂-aryl, NHCO₂-heteroaryl, NHCONH₂, NHCONH—C₁-C₆-alkyl, NHCONH-aryl,NHCONH-heteroaryl, SO₂—C₁-C₆-alkyl, SO₂-aryl, SO₂-heteroaryl, SO₂NH₂,SO₂NH—C₁-C₆-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, C₁-C₆-alkyl,C₃-C₆-cycloalkyl, CF₃, CH₂CF₃, CH₂Cl₂, CH₂OH, CH₂CH₂OH, CH₂NH₂,CH₂SO₂CH₃, tetrafluorophenyl and pentafluorophenyl.

[0104] The term “heterocyclic”, as used herein, refers toheterocycloalkyl and heteroaryl. The term “substituted heterocyclic”, asused herein, refers to substituted heterocycloalkyl and substitutedheteroaryl.

[0105] The term “C₁-C₆ alkoxy”, as used herein, refers to a C₁-C₆ alkylgroup, as previously defined, attached to the parent molecular moietythrough an oxygen atom. Examples of C₁-C₆-alkoxy include, but are notlimited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy,neopentoxy and n-hexoxy.

[0106] The term “C₁-C₃-alkylamino”, as used herein, refers to one or twoC₁-C₃-alkyl groups, as previously defined, attached to the parentmolecular moiety through a nitrogen atom. Examples of C₁-C₃-alkylaminoinclude, but are not limited to, methylamino, dimethylamino, ethylamino,diethylamino, and propylamino.

[0107] The term “alkylamino” refers to a group having the structure—NH(C₁-C₁₂ alkyl) where C₁-C₁₂ alkyl is as previously defined.

[0108] The term “dialkylamino” refers to a group having the structure—N(C₁-C₁₂ alkyl) (C₁-C₁₂ alkyl), where C₁-C₁₂ alkyl is as previouslydefined. Examples of dialkylamino are, but not limited to,dimethylamino, diethylamino, methylethylamino, piperidino, and the like.

[0109] The term “alkoxycarbonyl” represents an ester group, i.e. analkoxy group, attached to the parent molecular moiety through a carbonylgroup such as methoxycarbonyl, ethoxycarbonyl, and the like.

[0110] The term “carboxaldehyde”, as used herein, refers to a group offormula —CHO.

[0111] The term “carboxy”, as used herein, refers to a group of formula—COOH.

[0112] The term “carboxamide”, as used herein, refers to a group offormula —C(O)NH(C₁-C₁₂ alkyl) or —C(O)N(C₁-C₁₂ alkyl) (C₁-C₁₂ alkyl).

[0113] “Hydroxy protecting group”, as used herein, refers to an easilyremovable group which is known in the art to protect a hydroxyl groupagainst undesirable reaction during synthetic procedures and to beselectively removable. The use of hydroxy-protecting groups is wellknown in the art for protecting groups against undesirable reactionsduring a synthetic procedure and many such protecting groups are known,cf, for example, T. H. Greene and P. G. M. Wuts, Protective Groups inOrganic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).Examples of hydroxy protecting groups include, but are not limited to,methylthiomethyl, tert-dimethylsilyl, tert-butyldiphenylsilyl, acylsubstituted with an aromatic group and the like.

[0114] The term “protected hydroxy” refers to a hydroxy group protectedwith a hydroxy protecting group, as defined above, including benzoyl,acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, forexample.

[0115] “Aldehyde-protecting group”, as used herein, refers to an easilyremovable group which is known to protect an aldehyde group againstundesirable reaction during synthetic procedures and to be selectivelyremovable. The use of aldehyde-protecting groups is well known in theart for protecting aldehyde groups against undesirable reactions duringa synthetic procedure and many such protecting groups are known. See,for example, T. H. Greene and P. G. M. Wuts, Protective Groups inOrganic Synthesis. op. cit. Examples of aldehyde-protecting groupsinclude, but are not limited to, acetals, ketals, O-substitutedcyanohydrins, substituted hydrazones, imines and the like.

[0116] The term “protected aldehyde”, as used herein, refers to analdehyde group protected with an aldehyde-protecting group, as definedabove, including dimethyl acetyl, 1,3-dioxolane, 1,3-dioxane an thelike.

[0117] “Amino-protecting group”, as used herein, refers to an easilyremovable group which is known in the art to protect an amino groupagainst undesirable reaction during synthetic procedures and to beselectively removable. The use of amino-protecting groups is well knownin the art for protecting groups against undesirable reactions during asynthetic procedure and many such protecting groups are known, cf. forexample, T. H. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis op. cit. Examples of amino protecting groups include, but arenot limited to, 9-fluorenylmethyl carbamate, benzyl carbonate,tert-butyl carbonate, benzyl, p-toluene sulfonyl, acyl and the like.

[0118] The term “protected amino”, as used herein, refers to an aminogroup protected by an amino-protecting group, as defined herein.

[0119] The term “aprotic solvent”, as used herein, refers to a solventthat is relatively inert to proton activity, i.e., not acting as aproton-donor. Examples include, but are not limited to, hydrocarbons,such as hexane and toluene, for example, halogenated hydrocarbons, suchas, for example, methylene chloride, ethylene chloride, chloroform, andthe like, heterocyclic compounds, such as, for example, tetrahydrofuranand N-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such compounds are well known to those skilledin the art, and it will be obvious to those skilled in the art thatindividual solvents or mixtures thereof may be preferred for specificcompounds and reaction conditions, depending upon such factors as thesolubility of reagents, reactivity of reagents and preferred temperatureranges, for example. Further discussions of aprotic solvents may befound in organic chemistry textbooks or in specialized monographs, forexample: Organic Solvents Physical Properties and Methods ofPurification, 4th ed., edited by John A. Riddick et al., Vol. 1, in theTechniques of Chemistry Series, John Wiley & Sons, NY, 1986.

[0120] The term “protogenic organic solvent”, as used herein, refers toa solvent that tends to provide protons, such as an alcohol, forexample, methanol, ethanol, propanol, isopropanol, butanol, t-butanol,and the like. Such solvents are well known to those skilled in the art,and it will be obvious to those skilled in the art that individualsolvents or mixtures thereof may be preferred for specific compounds andreaction conditions, depending upon such factors as the solubility ofreagents, reactivity of reagents and preferred temperature ranges, forexample. Further discussions of protogenic solvents may be found inorganic chemistry textbooks or in specialized monographs, for example:Organic Solvents Physical Properties and Methods of Purification, 4thed., edited by John A. Riddick et al., Vol. 1, in the Techniques ofChemistry Series, John Wiley & Sons, NY, 1986.

[0121] Numerous asymmetric centers may exist in the compounds of thepresent invention. Except where otherwise noted, the present inventioncontemplates the various stereoisomers and mixtures thereof.Accordingly, whenever a bond is represented by a wavy line, it isintended that a mixture of stereo-orientations or an individual isomerof assigned or unassigned orientation may be present. Further, in thosecases where a bond between carbon atoms of the macrolide is a doublebond both the cis and trans forms are within the scope of the inventiondescribed in this application.

[0122] As used herein, the term “pharmaceutically acceptable salt”refers to those salts which are, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andlower animals without undue toxicity, irritation, allergic response andthe like, and are commensurate with a reasonable benefit/risk ratio.Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences 66: 1-19 (1977), incorporatedherein by reference. The salts can be prepared in situ during the finalisolation and purification of the compounds of the invention, orseparately by reacting the free base function with a suitable organicacid. Examples of pharmaceutically acceptable, nontoxic acid additionsalts are salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acidor by using other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate and aryl sulfonate.

[0123] As used herein, the term “pharmaceutically acceptable ester”refers to esters which hydrolyze in vivo and include those that breakdown readily in the human body to leave the parent compound or a saltthereof. Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.

[0124] The term “pharmaceutically acceptable prodrugs”, as used herein,refers to those prodrugs of the compounds of the present invention whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals with unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use,as well as the zwitterionic forms, where possible, of the compounds ofthe present invention. The term “prodrug” refers to compounds that arerapidly transformed in vivo to yield the parent compound of the aboveformula, for example by hydrolysis in blood. A thorough discussion isprovided in T. Higuchi and V. Stella, “Pro-drugs as Novel DeliverySystems, Vol. 14 of the ACS Symposium Series, and in Edward B. Roche,ed., “Bioreversible Carriers in Drug Design”, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

[0125] Antibacterial Activity.

[0126] Susceptibility tests can be used to quantitatively measure the invitro activity of an antimicrobial agent against a given bacterialisolate. Compounds were tested for in vitro antibacterial activity by amicro-dilution method. Minimal Inhibitory Concentration (MIC) wasdetermined in 96 well microfiter plates utilizing the appropriateMueller Hinton Broth medium (CAMHB) for the observed bacterial isolates.Antimicrobial agents were serially diluted (2-fold) in DMSO to produce aconcentration range from about 64 μg/ml to about 0.03 μg/ml. The dilutedcompounds (2 μl/well) were then spotted to sterile 96-well microtiterplates. The inoculum for each bacterial strain was adjusted to 5.5×10⁵CFU/ml in appropriate MIC medium; 200 μl/well of this inoculum was addedto the 96-well microtiter plate resulting in a final concentration of1×10⁵ CFU/ml. The 96 well plates were covered and incubated in ahumidified atmosphere at 35+/−2° C. for 16-24 hours depending on thebacterial strain tested. Following incubation, plate wells were visuallyexamined by Optical Density measurement for the presence of growth(turbidity). The lowest concentration of an antimicrobial agent at whichno visible growth occurs was defined as the MIC. The compounds of theinvention generally demonstrated an MIC in the range from about 64 μg/mlto about 0.03 μg/ml.

[0127] All in vitro testing follows the guidelines described in theApproved Standards M7-A5 protocol, published by the National Committeefor Clinical Laboratory Standards (NCCLS).

[0128] Pharmaceutical Compositions.

[0129] The pharmaceutical compositions of the present invention comprisea therapeutically effective amount of a compound of the presentinvention formulated together with one or more pharmaceuticallyacceptable carriers. As used herein, the term “pharmaceuticallyacceptable carrier” means a non-toxic, inert solid, semi-solid or liquidfiller, diluent, encapsulating material or formulation auxiliary of anytype. Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil; safflower oil; sesame oil; olive oil; corn oil andsoybean oil; glycols; such a propylene glycol; esters such as ethyloleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminun hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffersolutions, as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator. Thepharmaceutical compositions of this invention can be administered tohumans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), buccally, or as an oral or nasal spray.

[0130] Liquid dosage forms for oral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

[0131] Injectable preparations, for example, sterile injectable aqueousor oleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

[0132] The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

[0133] In order to prolong the effect of a drug, it is often desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissues.

[0134] Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

[0135] Solid dosage forms for oral administration include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound is mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier such as sodium citrate or dicalciumphosphate and/or: a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol, and silicic acid, b) binders such as, forexample, carboxymethyl cellulose, alginates, gelatin,polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such asglycerol, d) disintegrating agents such as agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain silicates, and sodiumcarbonate, e) solution retarding agents such as paraffin, f) absorptionaccelerators such as quaternary ammonium compounds, g) wetting agentssuch as, for example, cetyl alcohol and glycerol monostearate, h)absorbents such as kaolin and bentonite clay, and i) lubricants such astalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof. In the case of capsules,tablets and pills, the dosage form may also comprise buffering agents.

[0136] Solid compositions of a similar type may also be employed asfillers in soft and hard-filled gelatin capsules using such excipientsas lactose or milk sugar as well as high molecular weight polyethyleneglycols and the like.

[0137] The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

[0138] Dosage forms for topical or transdermal administration of acompound of this invention include ointments, pastes, creams, lotions,gels, powders, solutions, sprays, inhalants or patches. The activecomponent is admixed under sterile conditions with a pharmaceuticallyacceptable carrier and any needed preservatives or buffers as may berequired. Ophthalmic formulation, ear drops, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

[0139] The ointments, pastes, creams and gels may contain, in additionto an active compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

[0140] Powders and sprays can contain, in addition to the compounds ofthis invention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

[0141] Transdermal patches have the added advantage of providingcontrolled delivery of a compound to the body. Such dosage forms can bemade by dissolving or dispensing the compound in the proper medium.Absorption enhancers can also be used to increase the flux of thecompound across the skin. The rate can be controlled by either providinga rate controlling membrane or by dispersing the compound in a polymermatrix or gel.

[0142] According to the methods of treatment of the present invention,bacterial infections are treated or prevented in a patient such as ahuman or other animal by administering to the patient a therapeuticallyeffective amount of a compound of the invention, in such amounts and forsuch time as is necessary to achieve the desired result. By a“therapeutically effective amount” of a compound of the invention ismeant a sufficient amount of the compound to treat bacterial infections,at a reasonable benefit/risk ratio applicable to any medical treatment.It will be understood, however, that the total daily usage of thecompounds and compositions of the present invention will be decided bythe attending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular patientwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well known in the medical arts.

[0143] The total daily dose of the compounds of this inventionadministered to a human or other animal in single or in divided dosescan be in amounts, for example, from 0.01 to about 50 mg/kg body weightor more usually from 0.1 to about 25 mg/kg body weight. Single dosecompositions may contain such amounts or submultiples thereof to make upthe daily dose. In general, treatment regimens according to the presentinvention comprise administration to a patient in need of such treatmentof from about 10 mg to about 1000 mg of the compound(s) of thisinvention per day in single or multiple doses.

[0144] The pharmaceutical compositions of this invention can beadministered to fish by blending them in the fish feed to beadministered orally or may be dissolved in water in which sick fish areplaced to swim around (a method using a so-called “medicated bath”). Thedosage for the treatment of fish differs depending upon the purpose ofadministration (prevention or cure of disease) and type, size and extentof infection of the fish to be treated. Generally, a dosage of 5-1000mg, preferably 20-100 mg, per kg of body weight of fish may beadministered per day, either at one time or divided into several times.It will be recognized that the above-specified dosage is only a generalrange which may be reduced or increased depending on the age, bodyweight, condition of disease, etc. of the fish.

[0145] Abbreviations

[0146] Abbreviations which may be used in the descriptions of theschemes and the examples that follow are: Ac for acetyl; AIBN for2,2-azobisisobutyronitrile; Bn for benzyl; Boc for t-butoxycarbonyl;Bu3SnH for tributyltin hydride; Bz for benzoyl; CDI forcarbonyldiimidazole; DBU for 1,8-diazabicyclo [5.4.0]undec-7-ene; DCCfor 1,3-dicyclohexylcarbodiimide; DEAD for diethylazodicarboxylate; DICfor 1,3-diisopropylcarbodiimide; DIEA for diisopropylethylamine; DMAPfor dimethylaminopyridine; DMF for dimethyl formamide; DMSO fordimethylsulfoxide; DPPA for diphenylphosphoryl azide; EtOAc for ethylacetate; KHMDS for potassium bis (trimethylsilyl) amide; LDA for lithiumdiisopropyl amide; MeOH for methanol; Me₂S for dimethyl sulfide; MOM formethoxymethyl; OMs for mesylate; OTos for tosylate; NaN(TMS)₂ for sodiumbis(trimethylsilyl)amide; NCS for N-chlorosuccinimide; NMO for4-methylmorpholine N-oxide; PCC for pyridinium chlorochromate; PDC forpyridinium dichromate; Ph for phenyl; TEA for triethylamine; THF fortetrahydrofuran; TPP or PPh₃ for triphenylphosphine; TBS for tert-butyldimethylsilyl; and TMS for trimethylsilyl.

[0147] Synthetic Methods

[0148] The compounds and processes of the present invention will bebetter understood in connection with the following synthetic schemeswhich are illustrative of the methods by which the compounds of theinvention may be prepared. The groups L, X, R₁, R₂, and Rp are asdefined previously unless otherwise noted below.

[0149] Scheme 1 illustrates the processes for the synthesis of compoundsof formula I. The compounds of the present invention can be prepared bymethods which are well known in the art by modification of the readilyavailable compounds of formula (1.1) which can be prepared according tothe processes described by Baker et al. J. Org. Chem. 1988, 53,2340-2345; Elliott et al. J. Med. Chem. 1988, 41, 1651-1659; Ma et al.J. Med. Chem. 2001, 44, 4137-4156, and Or et al. U.S. Pat. No.6,075,011-B 1. Compounds of formula (1.1) are reacted with sulfonicanhydride, or sulfonyl chloride in an aprotic organic solvent such asmethylene chloride, ethylene chloride, THF, chloroform or the like at atemperature from about −78° C. to about 50° C. for about 30 minutes to48 hours in the presence of an amine base, such as pyridine,diethylamine, triethylamine or the like, optionally by adding a catalystsuch as DMAP, imidazole or the like to provide compounds of formula(1.2) where Z is a mesylate or a tosylate. Compounds of formula (13) areobtained by treating compounds of formula (1.2) with a base such as DBU,DIEA, triethylamine or the like in solvents such as acetone, DMF, DMSOat a temperature from 25° C. to 100° C. for about 1 hour to 48 hours.Compounds of formula (1.3) are reacted with an acylating reagent toprovide compounds of formulas (1.4) and (1.5). Typical acylatingconditions include reacting compounds of formula (1.3) with an acidanhydride, a mixed anhydride, an acid halide, a carboxylic acid and thelike, optionally in the presence of a catalyst such as DMAP, optionallyin the presence of a dehydration reagent such as DCC, DIC or the like,and optionally in the presence of a base such as sodium hydride,potassium tert-butoxide, LDA, KHMDS or the like, in an aprotic solventsuch as dichloromethane, chloroform, tetrahydrofuran,N-methylpyrrolidinone, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide or the like or amixture thereof at a temperature from −20° C. to 50° C. for 2-48 hours.A preferred acylating condition is reacting compounds of formula (1.3)with a carboxylic acid, DIC, and DMAP in dichloromethane at from 0° C.to room temperature. Compounds of formula (1.4), where Y is halogen oranother activating group such as mesylate, tosylate or the like, can beconverted to compounds of formula (1.5) by reacting with the anion ofR₂—X-M where R₂ and X are previously defined and M is sodium, potassium,lithium or the like, or R₂—X—H in the presence of a base such as sodiumhydride, potassium carbonate, LDA, sodium carbonate, DBU or the like inthe presence of an aprotic solvent such as tetrahydrofuran,N-methylpyrrolidinone, dimethylsulfoxide, N,N-dimethylformamide,N,N-dimethylacetamide, hexamethylphosphoric triamide or the like, or amixture thereof, at a temperature from −20° C. to 50° C. for 148 hours.Compounds of formula (1.5) undergo an intramolecular cyclization toprovide compounds of formula (I) upon treatment with a base such assodium hydride, potassium tert-butoxide, LDA, KHMDS or the like in anaprotic solvent such as tetrahydrofuran, N-methylpyrrolidinone,dimethylsulfoxide, N,N-dimethylformamide or the like, or a mixturethereof, at a temperature from −20° C. to 50° C. for 1-24 hours. The Rpprotecting group of the compounds of formula (1) can be removed upontreatment with methanol at from room temperature to 50° C. for 248hours.

EXAMPLES

[0150] The compounds and processes of the present invention will bebetter understood in connection with the following examples, which areintended as an illustration only and not limiting of the scope of theinvention. Various changes and modifications to the disclosedembodiments will be apparent to those skilled in the art and suchchanges and modifications including, without limitation, those relatingto the chemical structures, substituents, derivatives, formulationsand/or methods of the invention may be made without departing from thespirit of the invention and the scope of the appended claims.

Example 1

[0151] Compound of Formula (I): L=CH₂ CH₃, X=S, R₁=CH₃,R₂=2-[6-(dimethylamino-methyleneamino)purin-9-yl]-ethyl and Rp=H

[0152] Step 1a. Compound of Formula (1.1) of Scheme 1: R₁=CH₃ and Rp=Bz

[0153] A solution of a compound of formula (1.1) of Scheme 1, where R₁is CH₃ and Rp is H, (35.50 g, 62.17 mmol) and benzoyl anhydride (90%,15.47 g, 68.39 mmol) in methylene chloride (300 mL) was heated to refluxovernight. The reaction mixture was diluted with additional methylenechloride (500 mL) and washed with a saturated aqueous solution ofNaHCO₃, then with water and brine. The organic layers were dried overNa₂SO₄ and concentrated under reduced pressure to give the crude titlecompound (41.10 g, 98%).

[0154] MS (ESI) m/z 676 (M+H)⁺

[0155]¹³C-NMR (100 MHz, CDCl₃): δ 207, 175.5, 165.6, 162.3, 140.8,139.3, 134.5, 132.7, 131.5, 129.8, 128.7, 102.8, 80.0, 79.2, 76.6, 73.2,72.7, 72.1, 69.2, 64.0, 48.8, 44.0, 40.5, 37.7, 37.4, 37.0, 30.8, 21.1,20.5, 20.3, 17.0, 14.4, 13.4, 10.4, 8.0.

[0156] Step 1b. Compound of Formula (1.2) of Scheme 1: R₁=CH₃. Rp=Bz andZ=OMs

[0157] Into a solution of the compound from Stepla (5 g, 7.4 mmol) inpyridine (7 mL), was added methanesulfonic anhydride (MS20) (1.55 g,8.88 mmol) at room temperature. The reaction mixture was stirred at roomtemperature overnight. Additional Ms₂O (3.0 g, 17.6 mmol) was added. Themixture was stirred at room temperature for two days and at 45° C. for 6hours. The mixture was treated with saturated NaHCO₃ aqueous solutionand extracted with ethyl acetate. The organic layer was washed withsaturated NaHCO₃ aqueous solution and with brine, then dried (Na₂SO₄),filtered and concentrated under reduced pressure. The crude residue waspurified by flash chromatography (acetone:hexane, 3:7) to give 3.8 g ofthe title compound.

[0158] MS (ESI) m/z 754 (M+H)⁺

[0159]³C-NMR (125 MHz, CDCl₃): δ 206.8, 173.0, 165.2, 141.0, 132.5,130.7, 129.7, 128.1, 122.9, 100.3, 87.1, 80.1, 78.4, 72.9, 72.1, 68.6,63.4, 50.2, 43.6, 40.8, 40.7, 39.2, 38.9, 31.6, 31.5, 22.6, 21.9, 21.7,21.2, 20.9, 16.3, 14.0, 13.6, 10.6.

[0160] Step 1c. Compound of Formula (1.3) of Scheme 1: R₁=CH₃ and Rp=Bz

[0161] Into a solution of the compound from Step 1b (3.5 g, 4.64 mmol)in acetone (50 mL), was added DBU (1.4 mL, 9.28 mmol) at roomtemperature. The reaction mixture was stirred at 50° C. overnight thenat room temperature for one day. The mixture was taken up in ethylacetate, washed with saturated NaHCO₃ aqueous solution and with brine,then dried (Na₂SO₄), filtered and concentrated under reduced pressure togive 3.5 g of the crude title compound.

[0162] MS (ESI) m/z 658 (M+H)⁺

[0163] Step 1d. Compound of formula (1.4) of Scheme 1: R₁=CH₃, Rp=Bz andY=Cl Into a solution of the crude compound from Step 1c (1 g, 1.52 mmol)in dichloromethane (35 mL), chloroacetic acid (430 mg, 4.56 mmol) andDMAP (370 mg, 3.04 mmol) were added at room temperature. Into thereaction mixture a solution of DIC (714 μL, 4.56 mmol) indichloromethane (5 mL) was added slowly over 15 minutes. The reactionmixture was stirred at room temperature overnight. Additionalchloroacetic acid (288 mg, 3.04 mmol) and DIC (480 μL, 3.04 mmol) wereadded. The solid precipitate was removed by filtration and the filtratetreated with saturated NaHCO₃ aqueous solution and extracted with ethylacetate. The extract was washed with saturated NaHCO₃ aqueous solutionand with brine, then dried (Na₂SO₄), filtered and concentrated underreduced pressure. The crude residue was purified by flash chromatography(acetone:hexane, 1:4) to give the title compound (300 mg).

[0164] MS (ESI) m/z 734 (M+H)⁺

[0165]¹³C-NMR (125 MHz, CDCl₃): δ 206.8, 169.3, 165.4, 164.8, 145.7,138.5, 135.7, 132.8, 130.5, 129.6, 128.2, 124.6, 102.2, 84.8, 84.6,79.5, 77.5, 72.0, 69.3, 63.4, 49.9, 42.1, 40.8, 39.4, 37.3, 31.7, 31.5,23.4, 22.9, 22.6, 21.0, 20.6, 19.5, 18.6, 13.9, 11.6, 10.5.

[0166] Step 1e. Compound of Formula (1.5) of Scheme 1: X=S, R₁=CH₃,R₁=2-(6-amino-purin-yl)-ethyl and Rp=Bz

[0167] Into a solution of the compound from Step 1d (300 mg, 0.409 mmol)in acetone (3 mL), were added NaI (5 mg) and[6-amino-9H-purine]-1-ethanethiol (234 mg, (100 mg, 0.49 mmol) at roomtemperature. Into the resulting suspension, DBU (80 μL, 0.49 mmol) wasadded. The reaction mixture was stirred at room temperature for 3 hoursand treated with NaHCO₃ aqueous solution. The resulting mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated NaHCO₃ aqueous solution then with brine, and dried (Na₂SO₄),filtered and concentrated under reduced pressure. The crude residue waspurified by flash chromatography (dichloromethane:2M NH₃ inmethanol/98:2) to give the title compound (250 mg).

[0168] MS (ESI) m/z 893 (M+H)⁺

[0169]¹³C-NMR (125 MHz, CDCl₃): δ 207.2, 169.4, 167.8, 165.4, 155.4,152.9, 150.0, 145.6, 140.9, 138.5, 135.6, 132.8, 130.5, 129.6, 128.2,124.8, 119.6, 102.0, 84.5, 84.2, 79.5, 77.6, 72.0, 69.3, 63.4, 50.0,42.9, 40.8, 39.5, 37.3, 34.1, 32.5, 31.7, 31.6, 22.9, 22.6, 21.0, 20.7,19.5, 18.7, 14.1, 11.6, 10.6.

[0170] Step 1f. Compound of formula (1): L=CH₂CH₃, X=S, R₁=CH₃,R=2-[6-(dimethylamino-methyleneamino)purin-9-yl]-ethyl and Rp=Bz

[0171] Into a solution of the compound from Step 1e (30 mg, 0.033 mmol)in DMSO (0.8 mL) and THF(0.4 mL), was added potassium tert-butoxide (50μL 1.0 M solution in THF, 0.05 mmol) at 0° C. dropwise. The reactionmixture was stirred at 0° C. for 1 hour, then treated with saturatedNaHCO₃ aqueous solution. The resulting mixture was extracted with ethylacetate. The organic layer was washed with saturated NaHCO₃ aqueoussolution and with brine, then dried (Na₂SO₄), filtered and concentratedunder reduced pressure to give the title compound as a crude mixture (24mg).

[0172] MS (ESI) m/z 893 (M+H)⁺

[0173] Step 1g. Compound of Formula (1): L=CH₂CH₃, X=S, R₁=CH₃,R₂=2-[6-(dimethylamino-methyleneamino)purin-9-yl]-ethyl and Rp=H

[0174] A solution of the crude compound from Step 1f (24 mg) in methanol(2 mL) was heated to reflux overnight, cooled to room temperature andconcentrated under reduced pressure. The crude residue was purified byC₁₈ HPLC to give the title compound (2 mg).

[0175] MS (ESI) m/z 789 (M+H)⁺

[0176]¹³C-NMR (125 MHz, CDCl₃): δ 216.9, 176.0, 169.0, 155.0, 152.7,149.9, 146.0, 142.4, 123.3, 119.8, 104.9, 88.3, 83.4, 79.6, 78.4, 70.3,69.6, 65.9, 49.2, 47.8, 45.1, 41.9, 40.3, 38.8, 37.1, 35.8, 32.4, 29.7,28.5, 22.3, 21.3, 20.7, 18.0, 17.0, 15.4, 15.3, 13.0, 10.9.

Example 2

[0177] Compound of Formula (I): L=CH₂CH₃, X=S, R₁=CH₃,R₂=3-(3-pyridinyl)-1H-pyrazole-ethyl and Rp=H

[0178] Step 2a. Compound of Formula (1.5) of Scheme 1: X=S, R=CH₃,R₂=3-(3-pyridinyl)-1H-pyrazole-ethyl Rp=Bz

[0179] The title compound is obtained according to the proceduredescribed in Step 1e of Example 1 from the compound of Step 1d and[3-(3-pyridinyl)-1H-pyrazole]-1-ethanethiol (prepared as described inWO200216380-A1).

[0180] Step 2b. Compound of Formula (1): L=CH₂CH₃, X=S, R₁=CH₃,R₂=3-(3-pyridinyl)-1H-pyrazole-ethyl and Rp=Bz

[0181] The title compound is obtained from the compound of Step 2aaccording to the procedure described in Step 1f of Example 1.

[0182] Step 2c. Compound of Formula (1): L=CH₂CH₃, X=S, R₁=CH₃,R₂=3-(3-pyridinyl)-1H-pyrazole-ethyl and Rp=H

[0183] The title compound is obtained from the compound of Step 2baccording to the procedure described in Step 1g of Example 1.

Example 3

[0184] Compound of Formula (1): L=CH₂CH₃, X=S, R₁=CH₃,R₂=[3-(3-yridinyl)-1H-1,2,4-triazole-1-yl]-ethyl and Rp=H

[0185] Step 3a. Compound of Formula (1.5) of Scheme 1: X=S, R₁CH₃,R₂=[3-(3-pyridinyl)-1H-1,2,4-triazole-1-yl]-ethyl and Rp=Bz

[0186] The title compound is obtained from the compound of Step 1d ofExample 1 and [3-(3-pyridinyl)-1H-1,2,4-triazole-1-yl]-ethanethiol(prepared as described in WO200216380-A1) according to the proceduredescribed in Step 1e.

[0187] Step 3b. Compound of Formula (I): L=CH₂CH₃, X=S, R₁=CH₃.R₂=[3-(3-pyridinyl)-1H-1,2,4-triazole-1-yl]-ethyl and Rp=Bz

[0188] The title compound is obtained from the compound of Step 3aaccording to the procedure described in Step 1f of Example 1.

[0189] Step 3c. Compound of formula (1): L=CH₂CH₃, X=S, R₁=CH₃,R₂=[3-(3-pyrdinyl)-1H-1,2,4-triazole-1-yl]-ethyl and Rp=H

[0190] The title compound is obtained from the compound of Step 3baccording to the procedure described in Step 1 g of Example 1.

Example 4

[0191] Compound of Formula (1): L=CH₂CH₃, X=S, R₁=CH₃,R₂=[4-(3-pyridinyl)-1H-imidazole]-1-ethyl and Rp=H

[0192] Step 4a. Compound of Formula (1.5) of Scheme 1: X=S, R=CH₃,R₁=[4-(3-pyridinyl)-1H-imidazole]-1-ethyl and Rp=Bz

[0193] The title compound is obtained from the compound of Step 1d ofExample 1 and [4-(3-pyridinyl)-1H-imidazole]-1-ethanethiol (prepared asdescribed in WO200216380-A1) according to the proedure described in Step1e of Example 1.

[0194] Step 4b. Compound of Formula (I): L=CH₂CH₃, X=S, R₁=CH₃,R₂=[4(3-pyridinyl)-1H-imidazole]-1-ethyl and Rp=Bz

[0195] The title compound is obtained from the compound of Step 4aaccording to the procedure described in Step 1f of Example 1.

[0196] Step 4c. Compound of Formula (1): L=CH₂CH₃, X=S, R₁=CH₃,R₂=[4-(3-pyridinyl)-1H-imidazole]-1-ethyl and Rp=H

[0197] The title compound is obtained from the compound of Step 4baccording to the procedure described in Step 1g of Example 1.

[0198] Although the invention has been described in detail with respectto various preferred embodiments it is not intended to be limitedthereto, but rather those skilled in the art will recognize thatvariations and modifications may be made therein which are within thespirit of the invention and the scope of the appended claims

What is claimed is:
 1. A compound represented by the formula

and the pharmaceutically acceptable salts, esters and prodrugs thereof,wherein L is selected from the group consisting of: (1) —CH(OH)CH₃; (2)C₁-C₆ alkyl, optionally substituted with one or more substituentsselected from the group consisting of aryl, substituted aryl, heteroaryland substituted heteroaryl; (3) C₂-C₆ alkenyl, optionally substitutedwith one or more substituents selected from the group consisting ofaryl, substituted aryl, heteroaryl and substituted heteroaryl; and (4)C₂-C₆ alkynyl, optionally substituted with one or more substituentsselected from the group consisting of aryl, substituted aryl, heteroaryland substituted heteroaryl; R₁ is selected from the group consisting ofC₁-C₆-alkyl, C₂-C₆-alkenyl and C₂-C₆-alkynyl, each optionallysubstituted with one or more substituents selected from the groupconsisting of: (1) halogen; (2) aryl; (3) substituted aryl; (4)heteroaryl; (5) substituted heteroaryl; (6) —O—R₅, where R₅ is selectedfrom the group consisting of: a. hydrogen; b. aryl; c. substituted aryl;d. heteroaryl; and e. substituted heteroaryl; (7) —O—C₁-C₆-alkyl-R₅,where R₅ is as previously defined; (8) —O—C₂-C₆-alkenyl-R₅, where R₅ isas previously defined; (9) —O—C₂-C₆-alkynyl-R₅, where R₅ is aspreviously defined; and (10) —NR₆R₇, where R₆ and R₇ are eachindependently selected from the group consisting of: hydrogen;C₁-C₆-alkyl, optionally substituted with one or more substituentsselected from the group consisting of halogen, aryl, substituted aryl,heterocyclic and substituted heterocyclic; C₂-C₆-alkenyl, optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, aryl, substituted aryl, heterocyclic andsubstituted heterocyclic; and C₂-C₆-alkynyl, optionally substituted withone or more substituents selected from the group consisting of halogen,aryl, substituted aryl, heterocyclic and substituted heterocyclic; orR₆R₇ taken together with the nitrogen atom to which they are connectedform a 3- to 7-membered ring which may optionally contain one or morehetero functions selected from the group consisting of —O—, —NH—,—N(C₁-C₆-alkyl)-, —N(aryl)-, —N(heteroaryl)-, —S—, —S(O)— and —S(O)₂—;R₂ is selected from the group consisting of: (1) hydrogen; (2)C₁-C₆-alkyl, optionally substituted with one or more substituentsselected from the group consisting of: a. halogen; b. aryl; c.substituted aryl; d. heterocyclic; e. substituted heterocyclic; f.—O—R₃, where R₃ is selected from the group consisting of: i. hydrogen;ii. aryl; iii. substituted aryl; iv. heteroaryl; and v. substitutedheteroaryl; g. —O—C₁-C₆-alkyl-R₃, where R₃ is as previously defined; h.—O—C₂-C₆-alkenyl-R₃, where R₃ is as previously defined; i.—O—C₂-C₆-alkynyl-R₃, where R₃ is as previously defined; and j. —NR₆R₇,where R₆ and R₇ are as previously defined; (3) C₂-C₆-alkenyl, optionallysubstituted with one or more substituents selected from the groupconsisting of: a halogen; b. aryl; c. substituted aryl; d. heterocyclic;e. substituted heterocyclic; f. —O—R₃, where R₃ is as previouslydefined; g. —O—C₁-C₆-alkyl-R₃, where R₃ is as previously defined; h.—O—C₂-C₆-alkenyl-R₃, where R₃ is as previously defined; i.—O—C₂-C₆-alkynyl-R₃, where R₃ is as previously defined; and j. —NR₆R₇,where R₆ and R₇ are as previously defined; and (4) C₂-C₆-alkynyl,optionally substituted with one or more substituents selected from thegroup consisting of: a. halogen; b. aryl; c. substituted aryl; d.heterocyclic; e. substituted heterocyclic; f. —O—R₃, where R₃ is aspreviously defined; g. —O—C₁-C₆-alkyl-R₃, where R₃ is as previouslydefined; h. —O—C₂-C₆-alkenyl-R₃, where R₃ is as previously defined; i.—O—C₂-C₆-alkynyl-R₃, where R₃ is as previously defined; and j. —NR₆R₇,where R₆ and R₇ are as previously defined; X is selected from the groupconsisting of: (a) S(O)_(n), where n is 0, 1, or 2; (b) O; and (c) NR₅,where R₅ is as previously defined;  and Rp is hydrogen or a hydroxyprotecting group.
 2. A compound according to claim 1 wherein L isCH₂CH₃, X is —S—, R₁ is CH₃ and R₂ and Rp are as defined in claim
 1. 3.A compound according to claim 1 which is selected from the groupconsisting of: Compound of formula (1): L=CH₂CH₃, X=S, R₁=CH₃,R₂=2-[6-(dimethylamino-methyleneamino)purin-9-yl]-ethyl and Rp=H;Compound of formula (1): L=CH₂CH₃, X=S, R₁=CH₃,R₂=2-(6-amino-purin-yl)-ethyl and Rp=H; Compound of formula (1):L=CH₂CH₃, X=S, R₁=CH₃, R₂=3-(3-pyridinyl)-1H-pyrazole-ethyl and Rp=H;Compound of formula (1): L=CH₂CH₃, X=S, R₁=CH₃,R₂=[3-(3-pyridinyl)-1H-1,2,4-triazole-1-yl]-ethyl and Rp=H; Compound offormula (1): L=CH₂CH₃, X=S, R₁=CH₃,R₂==[4(3-pyridinyl)-1H-imidazole]-1-ethyl and Rp=H; and Compound offormula (I): L=CH₂CH₃, X=0, R₁=CH₃, R₂=CH₂CH₂-phenyl and Rp=H.
 4. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 1, or a pharmaceutically-acceptable salt, esteror prodrug thereof, in combination with a pharmaceutically acceptablecarrier.
 5. A method for controlling a bacterial infection in an animalcomprising administering to an animal a therapeutically-effective amountof a pharmaceutical composition according to claim
 4. 6. A process forpreparing a compound represented by the formula

wherein L, X, R₁, R₂, and Rp are as defined in claim 1, the methodcomprising (a) acylating a compound represented by the formula

 wherein L and R₁ are as defined in claim 1 and Rp is a hydroxyprotecting group, by reaction with a carboxylic acid, optionally in thepresence of a catalyst, optionally in the presence of a dehydrationreagent and optionally in the presence of a base in an aprotic organicsolvent to provide a product represented by the formula

 wherein L, R₁, and Rp are as defined in claim 1, and where Y ishalogen; (b) reacting a compound from step a with an anion of R₂-X-Mwhere R₂ and X are as defined in claim 1, Rp is a hydroxy protectinggroup and M is sodium, potassium, or lithium, or R₂-X—H in the presenceof a base in the presence of an aprotic solvent at a temperature from−20° C. to 50° C. for 148 hours to provide compound represented by theformula

 wherein L, R₁, R₂, Rp and X are as defined in claim 1; and (c) reactinga compound from step b with a base in organic solvent to effectcyclization to provide a compound of formula (I).